Evaluation of the Influence of Zhenwu Tang on the Pharmacokinetics of Digoxin in Rats Using HPLC-MS/MS.

Abstract

Digoxin (DIG) is a positive inotropic drug with a narrow therapeutic window that is used in the clinic for heart failure. The active efflux transporter of DIG, P-glycoprotein (P-gp), mediates DIG absorption and excretion in rats and humans. Up to date, several studies have shown that the ginger and Poria extracts in Zhenwu Tang (ZWT) affect P-gp transport activity. This study aimed to explore the effects of ZWT on the tissue distribution and pharmacokinetics of DIG in rats. The deionized water or ZWT (18.75 g/kg) was orally administered to male Sprague–Dawley rats once a day for 14 days as a pretreatment. On day 15, 1 hour after receiving deionized water or ZWT, the rats were given the solution of DIG at 0.045 mg/kg dose, and the collection of blood samples was carried out from the fundus vein or excised tissues at various time points. HPLC-MS/MS was used for the determination of the DIG concentrations in the plasma and the tissues under investigation. The pharmacokinetic interactions between DIG and ZWT after oral coadministration in rats revealed significant reductions in DIG Cmax and AUC0-∞, as well as significant increases in T1/2 and MRT0-∞. When coadministered with ZWT, the DIG concentration in four of the investigated tissues statistically decreased at different time points except for the stomach. This study found that combining DIG with ZWT reduced not only DIG plasma exposure but also DIG accumulation in tissues (heart, liver, lungs, and kidneys). The findings of our study could help to improve the drug's validity and safety in clinical applications and provide a pharmacological basis for the combined use of DIG and ZWT.